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Molecular basis of hereditary methaemoglobinaemia, types I and II: two novel mutations in the NADH‐cytochrome b 5 reductase gene
Author(s) -
Higasa Koichiro,
Manabe JunIchi,
Yubisui Toshitsuga,
Sumimoto Hideki,
Pungamritt Parichat,
Tanphaichitr Varavarn S.,
Fukumaki Yasuyuki
Publication year - 1998
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1998.01123.x
Subject(s) - missense mutation , mutant , nonsense mutation , mutation , reductase , enzyme , gene , mutant protein , biology , wild type , microbiology and biotechnology , chemistry , biochemistry , genetics
Hereditary methaemoglobinaemia, caused by deficiency of NADH‐cytochrome b 5 reductase (b5R), has been classified into two types, an erythrocyte (type I) and a generalized (type II). We analysed the b5R gene of two Thai patients and found two novel mutations. The patient with type II was homozygous for a C‐to‐T substitution in codon 83 that changes Arg (CGA) to a stop codon (TGA), resulting in a truncated b5R without the catalytic portion. The patient with type I was homozygous for a C‐to‐T substitution in codon 178 causing replacement of Ala (GCG) with Val (GTG). To characterize effects of this missense mutation, we investigated enzymatic properties of mutant b5R (Ala 178 Val). Although the mutant enzyme showed normal catalytic activity, less stability and different spectra were observed. These results suggest that this substitution influenced enzyme stability due to the slight change of structure. In conclusion, the nonsense mutation led to type II because of malfunction of the truncated protein. On the other hand, the missense mutation caused type I, due to degradation of the unstable mutant enzyme with normal activities in patient's erythrocytes, because of the lack of compensation by new protein synthesis during the long life‐span of erythrocytes.